The correlation between telomerase activity and the growth of human tumors has led to the hypothesis that continuous growth of advanced malignancies requires reactivation of telomerase. Hence, inhibitors of telomerase may represent a novel approach to cancer therapy. Here we propose to use oligonucleotides complementary to the RNA domain of telomerase to investigate antitelomerase therapeutic strategies and initiate clinical trials of antitelomerase therapy. Beginning trials will be facilitated by the fact that chemically similar oligonucleotides (but against different targets) are now being evaluated in lung cancer clinical trials. One of these compounds, ISIS 3521 has produced promising survival benefits when combined with systemic chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). The use of oligonucleotide approaches to inhibit telomerase in lung cancer has not been reported. Telomerase RNA is not a typical antisense target and offers many advantages relative to mRNA targets because its essential catalytic core is readily accessible to oligonucieotide binding. We have access to highly potent inhibitors from both Geron Corporation and ISIS Pharmaceuticals and will proceed into clinical trials with the inhibitor that appears to possess the most favorable properties based on our pre-clinical investigations. Both the Geron and ISIS compounds belong to families of oligonucleotides that possess improved pharmacokinetics. In addition to large-scale syntheses, these inhibitors are highly resistant to nucleases, are water soluble, acid resistant, and display high thermal stability of duplexes formed with RNA strands. The overall pre-clinical specific goal of this project is to combine chemistry and cell biology in an integrated effort to evaluate the effects of inhibiting telomerase with targeted oligonucleotides in lung tumors both in cell culture and in mice with tumor xenografts. Promising agents will complete studies of drug formulation and safety profile, experimental pharmacokinetics and animal toxicology in collaboration with our pharmaceutical partners to guide the conduct of clinical trials. Although it is expected that telomerase inhibitors will be most effective when treating minimal residual disease, we wilt focus first in advanced human disease by examining whether telomerase inhibitors work additively or Synergistically with standard chemotherapy. We anticipate conducting Phase I clinical and pharmacologic studies of promising antitelomerase inhibitors alone followed by combinations with chemotherapeutic agents in patients with advanced NSCLC with malignant pleural effusions. This strategy will allow us to test the efficacy of inhibiting telomerase in humans as well as determining potential side effects and best treatment schedule. These studies will be followed by Phase II efficacy trials in patients with advanced NSCLC. We anticipate these studies to provide clinical evidence on the importance of inhibiting telomerase to improve patient response and survival.